scholarly journals Automated Fitting of Transition State Force Fields for Biomolecular Simulations

2020 ◽  
Author(s):  
Olaf Wiest ◽  
Taylor R. Quinn ◽  
Himani Patel ◽  
Paul Helquist ◽  
Per-Ola Norrby ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Molecular Mechanics ◽  
Small Molecule ◽  
Functional Form ◽  
Enzymatic Reactions ◽  
Hmgcoa Reductase ◽  
Biomolecular Simulations ◽  
Pseudomonas Mevalonii ◽  
State Force

The application of the Quantum Guided Molecular Mechanics (Q2MM) method to transition states of enzymatic reactions to generate a transition state force field (TSFF) with the functional form of AMBER. The differences to fitting of small-molecule TSFFs and the similarities of the approach to transfer learning are discussed. The application to the transition state of the second hydride transfer in HMGCoA Reductase from Pseudomonas mevalonii is discussed. <br><br>

scholarly journals Automated Fitting of Transition State Force Fields for Biomolecular Simulations

2020 ◽  
Author(s):  
Olaf Wiest ◽  
Taylor R. Quinn ◽  
Himani Patel ◽  
Paul Helquist ◽  
Per-Ola Norrby ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Molecular Mechanics ◽  
Small Molecule ◽  
Functional Form ◽  
Enzymatic Reactions ◽  
Hmgcoa Reductase ◽  
Biomolecular Simulations ◽  
Pseudomonas Mevalonii ◽  
State Force

The application of the Quantum Guided Molecular Mechanics (Q2MM) method to transition states of enzymatic reactions to generate a transition state force field (TSFF) with the functional form of AMBER. The differences to fitting of small-molecule TSFFs and the similarities of the approach to transfer learning are discussed. The application to the transition state of the second hydride transfer in HMGCoA Reductase from Pseudomonas mevalonii is discussed. <br><br>

scholarly journals Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jessica Wahlers ◽  
Jèssica Margalef ◽  
Eric Hansen ◽  
Armita Bayesteh ◽  
Paul Helquist ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Molecular Mechanics ◽  
Bioactive Compounds ◽  
Palladium Catalyzed ◽  
The One ◽  
Nitrogen Nucleophiles ◽  
State Force ◽  
Selection Of

AbstractThe palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

scholarly journals Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

2021 ◽  
Author(s):  
Jessica Wahlers ◽  
Jessica Margalef ◽  
Eric Hansen ◽  
Armita Bayesteh ◽  
Paul Helquist ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Molecular Mechanics ◽  
Bioactive Compounds ◽  
Palladium Catalyzed ◽  
The One ◽  
Nitrogen Nucleophiles ◽  
State Force ◽  
Selection Of

Abstract The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

scholarly journals Transition State Force Field for the Asymmetric Redox-Relay Heck Reaction

2020 ◽  
Author(s):  
Anthony R. Rosales ◽  
Sean P. Ross ◽  
Paul Helquist ◽  
Per-Ola Norrby ◽  
Matthew S. Sigman ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Heck Reaction ◽  
State Force

scholarly journals Application of Q2MM to predictions in stereoselective synthesis

2018 ◽  
Vol 54 (60) ◽  
pp. 8294-8311 ◽  
Author(s):  
Anthony R. Rosales ◽  
Taylor R. Quinn ◽  
Jessica Wahlers ◽  
Anna Tomberg ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Transition State ◽  
Molecular Mechanics ◽  
Stereoselective Synthesis ◽  
Force Fields ◽  
Accurate Prediction ◽  
State Force

Transition state force fields derived by Quantum Guided Molecular Mechanics (Q2MM) allows the rapid and accurate prediction of stereoselectivity.

scholarly journals Stereoselectivity Predictions for the Pd-Catalyzed 1,4-Conjugate Addition Using Q2MM

2021 ◽  
Author(s):  
Jessica Wahlers ◽  
Michael Maloney ◽  
Farbod Salahi ◽  
Anthony Rosales ◽  
Paul Helquist ◽  
...  
Keyword(s):  
Transition State ◽  
Force Field ◽  
Conjugate Addition ◽  
Virtual Library ◽  
Title Reaction ◽  
State Force

The parameterization of a transition state force field for the title reaction is described. Validation for 82 literature examples leads to a MUE of 1.8 kJ/mol and an R2 of 0.877 between computed and experimental stereoselectivities. The use if the TSFF is demonstrated for a virtual library of 27 ligands and 59 enones. <br>

scholarly journals Microsecond Timescale Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues

2019 ◽  
Author(s):  
Taylor Quinn ◽  
Calvin N. Steussy ◽  
Brandon E. Haines ◽  
Jinping Lei ◽  
Wei Wang ◽  
...  
Keyword(s):  
Transition State ◽  
Molecular Mechanics ◽  
Conformational Changes ◽  
Enzymatic Catalysis ◽  
Dynamic Effect ◽  
Md Simulations ◽  
Site Directed Mutagenesis ◽  
Pseudomonas Mevalonii ◽  
Remote Residues ◽  
Coa Reductase

<p>Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. QM/MM methods have been extensively used to study these reactions, but the difficulties arising from the hybrid treatment of the system are well documented. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to react the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach the second hydride transfer transition state of HMG-CoA reductase from <i>Pseudomonas mevalonii </i>(<i>Pm</i>HMGR) identified three remote residues, R396 E399 and L407, (15-27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues.</p>

scholarly journals Microsecond Timescale Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues

2019 ◽  
Author(s):  
Taylor Quinn ◽  
Calvin N. Steussy ◽  
Brandon E. Haines ◽  
Jinping Lei ◽  
Wei Wang ◽  
...  
Keyword(s):  
Transition State ◽  
Molecular Mechanics ◽  
Conformational Changes ◽  
Enzymatic Catalysis ◽  
Dynamic Effect ◽  
Md Simulations ◽  
Site Directed Mutagenesis ◽  
Pseudomonas Mevalonii ◽  
Remote Residues ◽  
Coa Reductase

<p>Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. QM/MM methods have been extensively used to study these reactions, but the difficulties arising from the hybrid treatment of the system are well documented. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to react the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach the second hydride transfer transition state of HMG-CoA reductase from <i>Pseudomonas mevalonii </i>(<i>Pm</i>HMGR) identified three remote residues, R396 E399 and L407, (15-27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues.</p>

General Transition-State Force Field for Cytochrome P450 Hydroxylation

2007 ◽  
Vol 3 (5) ◽  
pp. 1765-1773 ◽  
Author(s):  
Patrik Rydberg ◽  
Lars Olsen ◽  
Per-Ola Norrby ◽  
Ulf Ryde
Keyword(s):  
Cytochrome P450 ◽  
Transition State ◽  
Force Field ◽  
State Force
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